Non-Coding DNA Variants May Link Early Exposures with Later Health Problems

John Stamatoyannopoulos, M.D. University of Washington NIEHS Grant U01ES0017156

Researchers, supported in part by NIEHS, report that genetic differences linked to a variety of diseases are activated during fetal development. These findings could help explain why some early environmental exposures increase disease risk years or even decades later.

The researchers investigated whether variants in noncoding regions of DNA regulate gene expression, by looking at thousands of these variants identified in genome-wide association studies (GWAS). They mapped regions that are sensitive to DNase I cleavage, because these hypersensitivity sites mark regions that actively regulate gene expression.

They found that more than 76 percent of noncoding GWAS variants were in, or very near, DNase I hypersensitivity sites, indicating that most of the noncoding variants in these samples regulate genes. In addition, 88 percent of the variants in regulatory DNA regions are active in fetal development, including variants associated with adult-onset disease. This suggests that environmental exposures during this period could influence risk for a large number of diseases.

The researchers also identified the genes regulated by hundreds of GWAS variants, including genes associated with blood platelet counts, amyotrophic lateral sclerosis (ALS), Crohn’s disease, breast and ovarian cancer, and schizophrenia. Almost 80 percent of GWAS variants in regulatory DNA were connected to genes that were not the closest ones to the variant, which is probably why previous attempts to link GWAS variants with target genes have been so difficult.